Bacterial meningitis is the most common serious infection of the central nervous system (CNS). Even with proper treatment, 3-25% of affected individuals may die or suffer permanent neurological sequelae including cerebral infarction, cerebral palsy, cognitive deficits, blindness, deafness or seizures. In order to produce meningitis, blood-borne bacteria must interact with and breech the blood-brain barrier (BBS). Penetration of the BBB by a bacterial pathogen is multifactorial and reflects a complex interplay between the host endothelium and microbial products. While experimental models of bacterial meningitis have clarified CNS pathways of brain inflammation and neuronal injury, much less is known about the specific response of BBB endothelium to the initial threat of an invading pathogen. I propose that the BBB is not merely a physical barrier but actively participates in the first line of host defense against the threat of bacterial pathogens. This proposal seeks to understand the immune function of the BBB against bacterial CNS entry, and why the BBB fails as a functional barrier during bacterial meningitis. I hypothesize that the BBB responds to bacteria by triggering a specific innate immune response to recruit neutrophils and prevent CNS infection. I postulate that the ability of pathogenic bacteria to enter inside brain endothelial cells disproportionately activates or dysregulates this response pathway, thereby contributing to BBB failure. Finally, I hypothesize that BBB function is thwarted specifically by meningitis causing bacteria. These hypotheses will be addressed in the following specific aims: Specific Aim 1: Characterize the innate immune response of the BBB for neutrophil signaling; Specific Aim 2: Assess the contribution of bacterial entry into brain endothelium to inflammatory dysregulation and BBB failure; Specific Aim 3: Investigate whether the BBB responds in a stereotypical of species-specific fashion to infection with different bacterial pathogens. [unreadable] [unreadable] [unreadable]